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The transcription factor ATOH 8 is regulated by erythropoietic activity and regulates HAMP transcription and cellular pSMAD 1,5,8 levels
Author(s) -
Patel Neeta,
Varghese Joe,
Masaratana Patarabutr,
LatundeDada Gladys O.,
Jacob Molly,
Simpson Robert J.,
McKie Andrew T.
Publication year - 2014
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.12649
Subject(s) - hamp , erythropoiesis , transcription factor , biology , smad , chromatin immunoprecipitation , transcription (linguistics) , microbiology and biotechnology , bone morphogenetic protein , promoter , gene expression , signal transduction , hepcidin , immunology , gene , biochemistry , medicine , anemia , linguistics , philosophy , inflammation
Summary ATOH8 has previously been shown to be an iron‐regulated transcription factor, however its role in iron metabolism is not known. ATOH8 expression in HEK 293 cells resulted in increased endogenous HAMP mRNA levels as well as HAMP promoter activity. Mutation of the E ‐box or SMAD response elements within the HAMP promoter significantly reduced the effects of ATOH 8, indicating that ATOH 8 activates HAMP transcription directly as well as through bone morphogenic protein ( BMP ) signalling. In support of the former, Chromatin immunoprecipitation assays provided evidence that ATOH 8 binds to E ‐box regions within the HAMP promoter while the latter was supported by the finding that ATOH 8 expression in HEK 293 cells led to increased phosphorylated SMAD 1,5,8 levels. Liver Atoh8 levels were reduced in mice under conditions associated with increased erythropoietic activity such as hypoxia, haemolytic anaemia, hypotransferrinaemia and erythropoietin treatment and increased by inhibitors of erythropoiesis. Hepatic Atoh8 mRNA levels increased in mice treated with holo transferrin, suggesting that Atoh8 responds to changes in plasma iron. ATOH 8 is therefore a novel transcriptional regulator of HAMP , which is responsive to changes in plasma iron and erythroid activity and could explain how changes in erythroid activity lead to regulation of HAMP .